Effects of cyclophosphamide on pulmonary function in patients with scleroderma and interstitial lung disease: a systematic review and meta-analysis of randomized controlled trials and observational prospective cohort studies

Nannini C, West CP, Erwin PJ, Matteson EL

CRD summary

The review evaluated the effectiveness of the prophylactic use of cyclophosphamide for pulmonary function in patients with scleroderma and interstitial lung disease. It found limited evidence for an improvement in forced vital capacity, but not for diffusing lung capacity for carbon monoxide. The review had no major flaws, but the authors considered the result not to be clinically significant.

Authors' objectives

To evaluate the effectiveness of the prophylactic use of cyclophosphamide for pulmonary function in patients with scleroderma and interstitial lung disease.

Searching

MEDLINE, EMBASE and The Cochrane Library were searched from 1986 to 2008 for publications in any language. Electronic databases of the annual meetings of European League Against Rheumatism, American College of Rheumatism and American Thoracic Society were searched from 1986 to 2008 for unpublished studies. Search terms were reported.

Study selection

Randomised controlled trials (RCTs) and prospective observational studies in which patients classed as having limited and/or diffuse scleroderma and interstitial lung disease were treated with oral or intravenous cyclophosphamide for at least 12 months were eligible for inclusion. The primary eligible outcomes were mean change in two pulmonary function tests: forced vital capacity or diffusing lung capacity for carbon monoxide (DLCO). Secondary outcomes were adverse events for the RCTs, which included: occurrence of infections that required antibiotic therapy; haemorrhagic cystitis; haematuria; and hospitalisation. Studies were not excluded if patients were also treated with corticosteroids.

Doses of cyclophosphamide varied between studies. Oral dose ranged from 1mg/kg/day to 2.5mg/kg/day. Intravenous dose in most studies ranged from 500mg/m2 to 750mg/m2 over varying time periods. Control groups in the included RCTs received placebo or azathioprine. Mean ages of patients in the included studies ranged from 37 to 55 years in RCTs and 37 to 50 years in observational studies. Mean length of follow-up was 12 months for all RCTs and 14.25 months (range 12 to 24 months) for observational studies.

Two independent researchers performed the study selection. Agreements were measured using the kappa statistic.

Assessment of study quality

Methodological quality was assessed by two reviewers independently using the Jadad scale (criteria included randomisation, blinding, allocation concealment, intention-to-treat analyses and completeness of follow-up) for RCTs and the Newcastle-Ottawa quality assessment scale for cohort studies. Disagreements were resolved by consensus.

Data extraction

Data were extracted in order to calculate the difference in forced vital capacity and DLCO predicted values between baseline and after 12 months of therapy. Results were expressed as a percentage of the normal predicted values based on the patient’s sex, age and height. Authors of the RCTs were contacted for missing data. The number of events for each outcome was extracted in order to calculate weighted mean differences (WMDs) for primary outcomes and relative risks (RR) and 95% confidence intervals (95%CI) for adverse events (secondary outcomes). Two independent reviewers performed the extraction.

Methods of synthesis

A random-effects model was used to combine WMDs and their 95%CIs. The results for the RCTs and cohort studies were analysed both separately and pooled. A subgroup analysis was performed using a test for interaction for studies of oral administration of cyclophosphamide versus studies with intravenous administration of cyclophosphamide. Where standard errors were not provided, mean values of the standard errors of the other studies were input and sensitivity analyses were performed across the range of reported standard errors of these studies. Statistical heterogeneity was determined using Χ2 and I2tests.

Results of the review

Nine relevant studies were identified, including three RCTs (n=263) and six prospective observational studies (n=117). Two RCTs had a Jadad score of 5 and one a score of 2. Two RCTs were double blind. The Newcastle-Ottawa scores of the observational studies were 4 or 5.

Overall pooled analysis of RCTs and observational studies showed improvements in forced vital capacity and DLCO after 12 months, but only the change in forced vital capacity was statistically significant (WMD 2.83%, 95% CI 0.35 to 5.31). There was evidence for statistical heterogeneity (p<0.00001). Separate analyses by type of study design indicated that there were no statistically significant differences in the RCTs for either outcome and there was evidence of significant statistical heterogeneity. By comparison, the observational studies indicated statistically significant improvements in both forced vital capacity (WMD 4.73%, 95% CI 0.74 to 8.73) and DLCO (WMD 7.48%, 95% CI 3.64 to 11.32), but these data were not presented graphically.

The changes in forced vital capacity and DLCO after 12 months did not differ between oral and intravenous cyclophosphamide administration. Sensitivity analyses did not significantly alter the results.

Limited data of adverse events were reported in the review.

Authors' conclusions

Cyclophosphamide treatment in patients with systemic sclerosis-related interstitial lung disease did not result in clinically significant improvement in lung function.

CRD commentary

The review addressed a well-defined question in terms of participants, interventions, study design and relevant primary outcomes. Relevant databases were searched in any language and unpublished studies were considered. The authors did not report cross-checking retrieved articles. Study selection, data extraction and validity assessment were carried out with efforts to reduce error and bias. Relevant study details were reported, but no details of the sex of patients were given. Statistical heterogeneity was assessed and there was evidence of heterogeneity. The statistical method used for the meta-analysis of the RCTs seemed appropriate, but available data for the RCTs was incomplete. A sensitivity analysis implied that the assumptions used for the meta-analysis were appropriate. This was a generally well-conducted piece of research, but limitations with a small number of studies and limited statistical data available for RCTs should be taken into consideration when interpreting the authors' conclusions. The authors considered that another limitation of the review was the concomitant use of corticosteroids.

Implications of the review for practice and research

Practice: The authors stated that since the results of their meta-analysis were based on 12 months of follow-up they might not reflect adverse events that developed over longer durations of treatment or follow-up.

Research: The authors identified a need for further RCTs with larger sample sizes and a need for studies of patients with worsening interstitial lung disease to investigate whether cyclophosphamide therapy might have a beneficial effect. Studies were also needed to determine the effect of cyclophosphamide alone in the absence of concomitant treatment with corticosteroids.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.